Many sodium channel blocking compounds have been previously identified and purified. For example, tetrodotoxin (“TTX”), also known as Ti Qu Duo Xin, Puffer Fish toxin, maculotoxin, spheroidine, tarichatoxin, tetrodontoxin, fugu poison and TTX (The Merck Index, 12th Ed. p 1578 (1996)), is a biological toxin found in puffer fish (Tetradontiae). The chemical name is octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethano-10aH-[1,3]dioxocino[6,5-d]pyrimidine-4,7,10,11,12-pentol with a molecular formula C11H17N3O8 and a molecular weight of 319.27. TTX is a potent non-protein neurotoxin and an indispensable tool drug for the study of neurobiology and physiology. TTX is a marine organic toxin which is mainly found in testicles, ovaries, eggs, livers, spleens, eyeballs, and blood of puffer fish as well as in diverse animal species, including goby fish, newt, frogs and the blue ringed octopus and even in marine algae. It is a known substance and production processes are known. Usually TTX is extracted from marine organisms (e.g. JP 270719 Goto and Takashi). Numerous extraction methods have been disclosed, for example, in U.S. Pat. No. 6,552,191, U.S. Pat. No. 6,478,966, U.S. Pat. No. 6,562,968 and US 2002/0086997, all hereby incorporated herein by reference. Synthesis of TTX has also been described and is well known to those skilled in the art (Kishi, Y. et al. J. Am. Chem. Soc. 1994, 94:9217-9221; Ohyabu, N. et al. J. Am. Chem. Soc. 2003, 125:8798-8805; and Hinman, A. et al. J. Am. Chem. Soc. 2003, 125:11510-11511).
TTX is known to be a highly potent and specific sodium channel blocker. Its biological activities and pharmacological properties have been the subject of numerous reviews, for example, Kao, Pharmacol. Rev. 18:997-1049 (1966); Tu, Anthony (Ed.) Handbook of Natural Toxins, Vol. 3: Marine Toxins and Venoms, pp. 185-210 (1988); and Narahashi, J. Toxicol. 20:67-84 (2001), all hereby incorporated by reference.
The use of TTX in pain management and treatment of drug addiction has been disclosed in, for example, WO 2002/022129 (Dong et al), CN 1,145,225 (Wang, et al), U.S. Pat. No. 5,846,975 (Pan et al), and U.S. Pat. No. 6,326,020 (Kohane et al). U.S. Pat. No. 6,407,088 to Dong et at describes the systemic application of tetrodotoxin in combination with suitable pharmaceutical vehicles to alleviate pain. U.S. Pat. No. 6,030,974 to Schwartz, et at describes a method of producing local anesthesia in a mammal experiencing pain in an epithelial tissue region. The method includes topically administering to the region, in a suitable pharmaceutical vehicle, an effective dose of a long-acting sodium channel blocking compound. Adams, et al., U.S. Pat. Nos. 4,022,899 and 4,029,793 pertain to a local anesthetic composition of tetrodotoxin or deoxytetrodotoxin, and another compound, generally a conventional local anesthetic compound or a similar compound having nerve-blocking properties.
Although TTX is safe and effective in treatment of various types of pain and drug addiction, TTX needs careful handling because of its pharmaceutical profile including the high level of toxicity and unique dosage window applicable to ensure safe and effective treatment with TTX. Additionally, not all patients respond well to TTX. Therefore alternative sodium channel blocking compounds that have unique properties and may have a different pharmaceutical profile would provide a useful alternative to treat and/or manage pain and/or drug addiction and thus would be desirable.